The present invention relates to a method and apparatus for reducing interstitial fluid pressure in tissue, particularly in tumors, and for removing interstitial fluid from confined spaces where drainage of such fluids is impaired, such as to reduce edema accumulation.
Throughout this application various publications are referenced and citations are provided in parentheses. The disclosure of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Cancer is the second leading cause of death in this country and still continues to be a public health problem of increasing significance (28). Cancer therapy may be categorized into three major approaches, surgical excision, radiotherapy and chemotherapy. Chemotherapy is defined as the treatment of cancer by a systemic administration of drugs.
Unfortunately, most drugs that showed promising effects in vitro have failed to be as effective in vivo, particularly in solid tumors. It has recently been proposed that one of the major reasons for this failure is the impediment of drug transport into tumors. In particular, a physiological barrier created by raised interstitial fluid pressure appears to be responsible. The interstitial fluid pressure is raised in tumors primarily because of the lack of lymphatics in tumors and the growth in confined spaces. The raised interstitial fluid pressure in tumors is a principal transport-retarding factor for the delivery of drugs such as macromolecules, i.e. large molecular weight molecules such as monoclonal antibodies (MoAb), tumor nucrosis factor and other chemotherapeutic agents.
Interstitial fluid accumulation is a known phenomenon in peritumoral areas in the brain and other organs, and where an adequate drainage system such as a lymphatic system is absent. This invention is aimed to facilitate clearance of interstitial fluid in circumstances such as brain edema from a variety of causes or lymphedema in the limbs after procedures such as mastectomy or lymphadenectomy.
Toxicity to normal tissues limits both the dose and frequency of drug administration. Antibody targeting specific tumor-associated antigens reduced some of the side effects of chemotherapy. Since the discovery of hybridoma technology by Kohler, G. and Milstein, C. (24), the application of MoAbs has rejuvenated efforts with chemotherapeutic treatment of tumors inaccessible as well as inoperable by moderate techniques. The monomer forms of basic immunoglobulin molecules range from 150 to 180 kd (4).
Use of MoAbs in the treatment of cancer is potentially very attractive. MoAbs bind very specifically to antigens. In cancer treatment, the theory is to use MoAbs that are specific to tumor-associated antigens. In attempts to enhance or extend therapeutic and diagnostic applications of MoAbs, MoAbs have been conjugated with radionuclides, toxins, drugs, cytokines, enzymes, effector antibodies, growth factors, biological response modifiers, extracellular matrix peptide products, immunotoxins, lymphokine activated killer cells, and tumor-infiltrating lymphocytes. (19).
MoAb therapy using conjugated pharmaceuticals, however, has not lived up to early expectations due to problems of hindered transport or delivery of MoAbs to tumors (See, e.g., 19, 21). Numerous factors can affect MoAb delivery. Jain et al. (16, 17, 18, 21) have emphasized the importance of an Interstitial Fluid Pressure (IFP) barrier against the effective transport of macromolecules such as MoAbs.
The large permeability resulting from the number of fenestrated capillaries and low hyaluronic acid content in the tumor interstitial fluid should, in principle, improve the transport of therapeutic drugs. In reality, however, the delivered fraction of infused dosage has not been up to the expected level. Heterogeneous blood flow, binding hindrance at the cell surface and heterogeneous antigen distribution, particularly in MoAb delivery, are not reasons enough to explain retarded transport in tumor tissue (22).
Jain et al. (19, 21) suspected that elevated Interstitial Fluid Pressure (IFP) is a principal transport retarding factor in MoAb delivery because of the lack of lymphatics in the tumor. In normal tissue, maintenance of the fluid balance within the tissue spaces is dependent upon the interplay of hydrostatic and colloid osmotic pressures operating on a vascular network with uneven permeability and with dissimilar exchange area with the aid of the lymphatic system. The lymphatics are responsible for macromolecular circulation throughout the body. Most macromolecules including proteins cannot return to the circulation without the lymphatic system after they percolate through the endothelial wall (11). Accordingly, lymphatic drainage is a factor of primary importance in maintaining fluid balance (12). Once the equilibrium is disrupted, dehydration or edema in the tissue would result from the imbalanced colloid osmotic and hydrostatic vascular pressure. These relations are well described by Starling's hypothesis (29).
A functioning lymphatic system as an anatomical entity has not been demonstrated in the tumor. The absence of lymphatics affords no alternative way circulating macromolecules can re-enter the circulation after their extravasation through capillary. The potential of fluid flow into the tumor is hindered by the opposing force with equivalent magnitude from IFP. This opposite force increases the IFP until all the forces in Starling's Law are balanced. Consequently, the interstitial fluid within the tumor becomes trapped. The fluid with MoAb therapeutic agents has insufficient force to flow into the tumor except for the slow advance by molecular diffusion because of a concentration gradient. Instead, it oozes out toward the tumor surface by the effective convection, diffusion and draining advantage by lymphatics at the tumor periphery. This outward fluid velocity at the tumor periphery additionally hinders the diffusional movement of molecules into the tumor center (19). Decreased intravascular pressure and/or increased interstitial pressure in tumors has been demonstrated by several investigators (1, 9, 14, 31, 37, 41).
Findings to date indicate that elevated IFP has been attributed to the absence of a well-defined lymphatic system in the tumor (5, 21), and to increased permeability of tumor vessels (16, 20). Researchers reported that IFP increases with tumor size (13, 30, 38, 42). The increase in IFP has also been shown to correlate with reduction in tumor blood flow (lower blood perfusion rate) and the development of necrosis in a growing tumor (13, 15, 30, 38).
Jain et al. (22) presented a mathematical model describing the possible relationship between the distribution of monoclonal antibody and elevated interstitial pressure. They proposed that enhanced IFP might be responsible for the poor penetration of MoAbs into tumors including the heterogeneous blood perfusion, hindered diffusion in the interstitium, and extravascular binding of MoAbs. Furthermore, they stated that the elevated interstitial pressure principally reduces the driving force for extravasation of fluid and macromolecules in tumors, and leads to an experimentally verifiable, radially outward convection which opposed the inward diffusion. They have presented results from several mathematical models and the models' implications (3, 17, 19, 21) to support their hypothesis.
Several investigators (10, 23, 32, 34) have attempted to increase Blood Perfusion Rate (BPR) via administration of vasoactive agents such as angiotensin and interleukin. In addition, radiation and heat treatment has been shown to increase the tumor blood flow. A key problem with these approaches is that the increase in blood flow is short-lived and usually confined to well vascularized regions (17, 19, 21). Osmotic agents as mannitol have also been used to reduce IFP by exerting higher vascular osmotic pressure (17, 19, 21, 33).